WO2007059963A1 - Formes cristallines f, g, h, i et k du mésylate d’imatinib - Google Patents

Formes cristallines f, g, h, i et k du mésylate d’imatinib Download PDF

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Publication number
WO2007059963A1
WO2007059963A1 PCT/EP2006/011240 EP2006011240W WO2007059963A1 WO 2007059963 A1 WO2007059963 A1 WO 2007059963A1 EP 2006011240 W EP2006011240 W EP 2006011240W WO 2007059963 A1 WO2007059963 A1 WO 2007059963A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
acid addition
addition salt
methanesulfonic acid
Prior art date
Application number
PCT/EP2006/011240
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English (en)
Inventor
Michael Mutz
Original Assignee
Novartis Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0524062A external-priority patent/GB0524062D0/en
Priority claimed from GB0524061A external-priority patent/GB0524061D0/en
Priority to KR1020137031545A priority Critical patent/KR20130137721A/ko
Priority to BRPI0618993-8A priority patent/BRPI0618993A2/pt
Priority to JP2008541641A priority patent/JP5844508B2/ja
Priority to CN2006800440077A priority patent/CN101312960B/zh
Priority to CA2628330A priority patent/CA2628330C/fr
Priority to EP06818763A priority patent/EP1960380A1/fr
Priority to AU2006316823A priority patent/AU2006316823A1/en
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to KR1020137031544A priority patent/KR20130140909A/ko
Priority to US12/094,629 priority patent/US7893076B2/en
Priority to KR1020137031543A priority patent/KR20130141712A/ko
Publication of WO2007059963A1 publication Critical patent/WO2007059963A1/fr
Priority to NO20082684A priority patent/NO20082684L/no
Priority to US13/006,505 priority patent/US8198289B2/en
Priority to AU2011201286A priority patent/AU2011201286A1/en
Priority to US13/183,572 priority patent/US8592440B2/en
Priority to US13/183,600 priority patent/US8846706B2/en
Priority to US13/183,557 priority patent/US8507515B2/en
Priority to US13/472,000 priority patent/US8633213B2/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention relates to particular crystal forms of the methanesulfonic acid addition salt of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl]- benzamide (the compound of formula I 1 see below), certain processes for their preparation, pharmaceutical compositions containing these crystal forms, and their use in diagnostic methods or, preferably, for the therapeutic treatment of warm-blooded animals, especially humans, and their use as an intermediate or for the preparation of pharmaceutical preparations for use in diagnostic methods or, preferably, for the therapeutic treatment of warm-blooded animals, especially humans.
  • lmatinib mesylate also known as lmatinib mesylate or STI571, the alpha and the beta crystal form thereof, as well as its pharmaceutical use are described in US 6,894,051.
  • lmatinib mesylate is the active ingredient of the drug Gleevec® (Glivec®) which is an approved medicament for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stromal tumors (GIST).
  • Glivec® is an approved medicament for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stromal tumors (GIST).
  • Glivec® is an approved medicament for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stromal tumors (GIST).
  • Hi-form Another polymorph of lmatinib mesylate, the so- called Hi-form, is described in WO2004/106326.
  • the invention relates especially to essentially pure crystal forms, preferably those which are referred to hereinafter as the F-crystal form, G-crystal form, H-crystal form, l-crystal form and K-crystal form of the methanesulfonic acid addition salt of lmatinib of formula I,
  • the F-crystal form of the methanesulfonic acid addition salt of a compound of formula I is characterized by lines in the X-ray diffraction diagram observed at an angle of refraction 2theta of 8.4° and 8.6°.
  • Fig. 1 shows the X-ray diffraction diagram of the F-crystal form of the methanesulfonic acid addition salt of a compound of formula I.
  • the angle of refraction 2theta is plotted on the horizontal axis (x-axis) and the relative line intensity (background-corrected peak intensity) on the vertical (y-axis).
  • the strongest line in the X- ray diffraction diagram is observed at an angle of refraction 2theta of 20.9°. More broadly, the F-crystal form is characterized by refractions at angles of refraction 2theta of 8.4°, 8.6°, 13.3°, 16.2°, 16.8°, 17.1°, 19.5°, 20.9°, 23.6° and 24.5°.
  • the G-crystal form of the methanesulfonic acid addition salt of a compound of formula I is characterized by a line in the X-ray diffraction diagram observed at an angle of refraction 2theta of 10.5° together with the absence of any lines between an angle of refraction 2theta of 4° and 8°.
  • Fig. 2 shows the X-ray diffraction diagram of the G-crystal form of the methanesulfonic acid addition salt of a compound of formula I.
  • the angle of refraction 2theta is plotted on the horizontal axis (x-axis) and the relative line intensity (background-corrected peak intensity) on the vertical (y-axis).
  • the G-crystal form is characterized by refractions at angles of refraction 2theta of 10.5°, 15.0°, 17.2°, 18.1°, 18.7°, 19.2°, 21.1° and 21.3°.
  • the H-crystal form of the methanesulfonic acid addition salt of a compound of formula I is characterized by a line in the X-ray diffraction diagram observed at an angle of refraction 2theta of 32.9°.
  • Fig. 3 shows the X-ray diffraction diagram of the H-crystal form of the methanesulfonic acid addition salt of a compound of formula I.
  • the angle of refraction 2theta is plotted on the horizontal axis (x-axis) and the relative line intensity (background-corrected peak intensity) on the vertical (y-axis).
  • the H-crystal form is dominated by a line at an angle of refraction 2theta of 25.1 °. More broadly, the H-crystal form is characterized by refractions at angles of refraction 2theta of 10.5°, 22.8°, 25.1 ° and 32.9°.
  • essentially pure material of the H-crystal form of the methanesulfonic acid addition salt of a compound of formula I 1 lines can be observed at angles of refraction 2theta 10.5°, 13.8°, 15.7°, 18.1 °, 21.0°, 22.8°, 24.3°, 25.1°, 26.3°, 29.7° and 32.9°.
  • the l-crystal form of the methanesulfonic acid addition salt of a compound of formula I is characterized by a line in the X-ray diffraction diagram observed at an angle of refraction 2theta of 12.9° together with the absence of any lines at an angle of refraction 2theta below 9° and above 29°.
  • Fig. 4 shows the X-ray diffraction diagram of the l-crystal form of the methanesulfonic acid addition salt of a compound of formula I.
  • the angle of refraction 2theta is plotted on the horizontal axis (x-axis) and the relative line intensity (background-corrected peak intensity) on the vertical (y-axis).
  • the l-crystal form is characterized by refractions at angles of refraction 2theta of 12.9°, 14.1°, 17.1°, 18.0°, 18.7°, 19.1 °, 19.8°, 20.9°, 23.9°, 24.3° and 25.2°.
  • the K-crystal form of the methanesulfonic acid addition salt of a compound of formula I is characterized by a line in the X-ray diffraction diagram observed at an angle of refraction 2theta of 37.9°.
  • Fig. 5 shows the X-ray diffraction diagram of the K-crystal form of the methanesulfonic acid addition salt of a compound of formula I.
  • the angle of refraction 2theta is plotted on the horizontal axis (x-axis) and the relative line intensity (background-corrected peak intensity) on the vertical (y-axis).
  • the K-crystal form is further characterized by a line at an angle of refraction 2theta of 21.0°. More broadly, the K-crystal form is characterized by refractions at angles of refraction 2theta of 12.1°, 14.1°, 18.2°, 18.4°, 21.0°, 23.4° and 28.4°.
  • essentially pure is understood in the context of the present invention to mean especially that at least 90, preferably at least 95, and most preferably at least 99 per cent by weight of the crystals of an acid addition salt of formula I are present in the specified crystal form according to the invention.
  • the term "essentially” means that at least the major lines of the diagram depicted in Fig. 1 , i.e. those having a relative line intensity of more than 20%, especially more than 30 %, as compared to the most intense line in the diagram, have to be present.
  • the F-crystal form of the methanesulfonic acid addition salt of a compound of formula I is characterized by a DSC curve showing a melting event at 95°C followed by an exothermic recrystallization and a second melting at about 223°C.
  • the essentially pure methanesulfonic acid addition salt of a compound of formula I in the F-crystal form shows the X-ray diffraction diagram indicated in Fig. 1.
  • the term "essentially” means that at least the major lines of the diagram depicted in Fig. 2, i.e. those having a relative line intensity of more than 20%, especially more than 30 %, as compared to the most intense line in the diagram, have to be present.
  • the essentially pure methanesulfonic acid addition salt of a compound of formula I in the G-crystal form shows the X-ray diffraction diagram indicated in Fig. 2.
  • the term "essentially” means that at least the major lines of the diagram depicted in Fig. 3, i.e. those having a relative line intensity of more than 20%, especially more than 30 %, as compared to the most intense line in the diagram, have to be present.
  • the essentially pure methanesulfonic acid addition salt of a compound of formula I in the H-crystal form shows the X-ray diffraction diagram indicated in Fig. 3.
  • the H-crystal form of the methanesulfonic acid addition salt of a compound of formula I which shows an X-ray diffraction diagram of the type shown in Fig. 3, in which the relative peak intensities of each peak do not deviate by more than 10% from the relative peak intensities in the diagram shown in Fig. 3, especially an X-ray diffraction diagram identical to that shown in Fig. 3.
  • the term "essentially" means that at least the major lines of the diagram depicted in Fig. 4, i.e. those having a relative line intensity of more than 20%, especially more than 30 %, as compared to the most intense line in the diagram, have to be present.
  • the essentially pure methanesulfonic acid addition salt of a compound of formula I in the l-crystal form shows the X-ray diffraction diagram indicated in Fig. 4.
  • the term "essentially” means that at least the major lines of the diagram depicted in Fig. 5, i.e. those having a relative line intensity of more than 20%, especially more than 30 %, as compared to the most intense line in the diagram, have to be present.
  • the essentially pure methanesulfonic acid addition salt of a compound of formula I in the K-crystal form shows the X-ray diffraction diagram indicated in Fig. 5.
  • the invention expressly relates also to those forms of the methanesulfonic acid addition salt of a compound of formula I in which crystals of the F-crystal form, G-crystal form, H-crystal form, l-crystal form and K-crystal form are present along with other crystal forms, in particular the ⁇ -crystal form, the ⁇ -crystal form, and/or the amorphous form of the lmatinib mesylate.
  • One utility of the F-crystal form, G-crystal form, H-crystal form, l-crystal form and K-crystal form of the methanesulfonic acid addition salt of a compound of formula I is the use as an intermediate for the preparation of a distinct crystal form of the methanesulfonic acid addition salt of a compound of formula I, especially the ⁇ -crystal form.
  • the (preferably essentially pure) ⁇ -crystal form is obtainable by a) digesting the F-crystal form , G-crystal form, H-crystal form, l-crystal form or the K-crystal form of the methanesulfonic acid addition salt of a compound of formula I with a suitable polar solvent, especially an alcohol, most especially methanol, or also a ketone (especially in a mixture with water, for example water/acetone), typically acetone, a N,N-di-lower alkyl- lower alkanecarboxamide, typically N,N-dimethylformamide or -acetamide, or a hydrophilic ether, typically dioxane, preferably in the presence of some water, or mixtures thereof, in suspension at a suitable temperature, preferably a temperature between 20 and 50°C, for example at about 25°C, or b) dissolving the F-crystal form, G-crystal form, H-crystal form,
  • distinct crystal forms are prone to incorporate distinct impurities upon crystallization, i.e. an impurity incorporated in crystal form ⁇ is not necessarily also incorporated in the F-crystal form, G-crystal form, H-crystal form, l-crystal form or K-crystal form.
  • an impurity incorporated in crystal form ⁇ is not necessarily also incorporated in the F-crystal form, G-crystal form, H-crystal form, l-crystal form or K-crystal form.
  • distinct crystal forms display different physical properties such as melting points, hygroscopicities, solubilities, flow properties or thermodynamic stabilities, and, hence, distinct crystal forms allow the choice of the most suitable form for a certain use or aspect, e.g. the use as an intermediate in the process of drug manufacture or in distinct administration forms like tablets, capsules, ointments or solutions.
  • the F-crystal form, G-crystal form, H-crystal form, l-crystal form and K-crystal form of the methanesulfonic acid addition salt of a compound of formula I possess valuable pharmacological properties and may, for example, be used as an anti-tumour agent or as an agent to treat restenosis.
  • the present invention relates especially to the F-crystal form, G-crystal form, H-crystal form, l-crystal form and K-crystal form of the methanesulfonic acid addition salt of a compound of formula I in the treatment of one of the said diseases mentioned herein or in the preparation of a pharmacological agent for the treatment thereof.
  • the antiproliferative, especially anti-tumour, activity of the methanesulfonic acid addition salt of a compound of formula I in vivo is, for example, described for the treatment of abl- dependent tumours in Nature Med. 2, 561-6 (1996).
  • the invention relates also to a method for the treatment of warm-blooded animals suffering from said diseases, especially leukemia, wherein a quantity of the F-crystal form , G-crystal form, H-crystal form, l-crystal form or K-crystal form of the methanesulfonic acid addition salt of a compound of formula I which is effective against the disease concerned, especially a quantity with antiproliferative efficacy, is administered to warm-blooded animals in need of such treatment.
  • the invention relates moreover to the use of the F-crystal form, G-crystal form, H-crystal form, l-crystal form and K-crystal form of the methanesulfonic acid addition salt of a compound of formula I for the preparation of pharmaceutical compositions for use in treating the human or animal body, especially for the treatment of tumours, such as gliomas or prostate tumours.
  • the present invention relates to the use in of the F-crystal form, G-crystal form, H-crystal form, l-crystal form and K-crystal form of the methanesulfonic acid addition salt of a compound of formula I in the treatment of one of the disorders listed below:
  • ALL Philadelphia chromosome-positive acute lymphocytic leukemia
  • glioblastoma multiforme preferably in combination with hydroxyurea
  • DFSP dermatofibrosarcoma protuberans
  • HES hypereosinophilic Sindrome
  • CMML chronic myelomonocytic leucemia
  • effective doses for example daily doses of about 50-2500 mg, preferably 100-1000 mg, especially 250-800 mg, of lmatinib having the F-crystal form G- crystal form, H-crystal form, l-crystal form or the K-crystal form, are administered to warmblooded animals of about 70 kg bodyweight.
  • daily dosages of 400 mg or 600 mg are administered orally once daily, preferably together with a meal and a large glass of water (about 200 mL).
  • 800 mg daily dosages are preferably administered in the form of 400 mg dosages twice daily together with food.
  • the F-crystal form, G-crystal form, H-crystal form, l-crystal form and K-crystal form described herein can be utilized to prepare stable pharmaceutical dosage forms.
  • the invention relates also to pharmaceutical preparations which contain an amount, especially an effective amount for prevention or treatment of one of the diseases mentioned herein, of the methanesulfonic acid addition salt of a compound of formula I in the F-crystal form, G- crystal form, H-crystal form, l-crystal form or K-crystal form, together with pharmaceutically acceptable carriers which are suitable for topical, enteral, for example oral or rectal, or parenteral administration and may be inorganic or organic and solid or liquid.
  • diluents for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycerin
  • lubricants for example silica, talc, stearic acid, or salts thereof, typically magnesium or calcium stearate, and/or polyethylene glycol, are used for oral administration.
  • Tablets may likewise contain binders, for example magnesium aluminium silicate, starches, typically corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if so desired, disintegrants, for example starches, agar, alginic acid, or a salt thereof, typically sodium alginate, and/or effervescent mixtures, or adsorbents, colouring agents, flavours, and sweetening agents.
  • binders for example magnesium aluminium silicate, starches, typically corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if so desired, disintegrants, for example starches, agar, alginic acid, or a salt thereof, typically sodium alginate, and/or effervescent mixtures, or adsorbents, colouring agents, flavours, and sweetening agents.
  • Such solutions are preferably isotonic aqueous solutions or suspensions, these possibly being prepared before use, for example in the case of lyophilised preparations containing the active substance either alone or together with a carrier, for example mannitol.
  • the pharmaceutical substances may be sterilised and/or may contain excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for the regulation of osmotic pressure, and/or buffers.
  • the present pharmaceutical preparations which, if so desired, may contain further pharmacologically active substances, are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilising processes, and contain from about 1% to 100%, especially from about 1% to about 20%, of the active substance or substances.
  • the tablet or capsule contains 50 mg 100 mg of the of the methanesulfonic acid addition salt of a compound of formula I in the F-crystal form, G-crystal form, H-crystal form, l-crystal form or K-crystal form, optionally together with pharmaceutically acceptable carriers.
  • the capsule is a hard gelatine capsule containing a dry powder blend.
  • the capsule shell preferably contains gelatine and titanium dioxide as well as red iron oxide.
  • the ratio of weight of capsule fill to capsule shell is preferably between about 100:25 and 100:50, more preferably between 100:30 and 100:40.
  • a film coated tablet comprising 100 mg, 400 mg or 800 mg drug substance together with inactive excepients selected from colloidal anhydrous silica, polyvinylpyrrolidone, magnesium stearate and microcrystalline cellulose.
  • inactive excepients selected from colloidal anhydrous silica, polyvinylpyrrolidone, magnesium stearate and microcrystalline cellulose.
  • Example 1 Preparation of crystalline form F of lmatinib Mesylate using Benzyl Alcohol
  • lmatinib mesylate is first dissolved in about 100ml of water. About 50 ⁇ l of the stock solution is dispensed manually into a CRISSY 96-well block, to have a total amount of drug substance of 5mg per well. The solution is flushed with nitrogen at room temperature to dry the solution. The dry precipitate is resuspended with 250 ⁇ l of benzyl alcohol. The suspension or solution is agitated using High-speed vortexer at about 45-55°C for about 2 hrs. The solution is then allowed to evaporate at 45°C to 55°C under a stream of nitrogen.
  • Example 2 Preparation of crystalline form F of lmatinib Mesylate using a mixture of Benzyl Alcohol and Ethyl Acetate
  • lmatinib mesylate is first dissolved in about 100ml of water. About 50 ⁇ l of the stock solution is dispensed manually into a CRISSY 96-well block, to have a total amount of drug substance of 5mg per well. The solution is flushed with nitrogen at room temperature to dry the solution. The dry precipitate is resuspended with a mixture of 222 ⁇ l of benzyl alcohol and 28 ⁇ l of ethyl acetate. The suspension or solution is agitated using High-speed vortexer at about 45-55°C for about 2 hrs. The solution is then allowed to evaporate at 45°C to 55°C under a stream of nitrogen.
  • Example 3 Preparation of crystalline form F of lmatinib Mesylate using a mixture of Benzyl Alcohol and 1 ,4-Dioxane, 3-Pentanone or Diisopropyl Ether
  • lmatinib mesylate is first dissolved in about 100ml of water. About 50 ⁇ l of the stock solution is dispensed manually into a CRISSY 96-well block, to have a total amount of drug substance of 5mg per well. The solution is flushed with nitrogen at room temperature to dry the solution. The dry precipitate is resuspended with a mixture of 214 ⁇ l of benzyl alcohol and 36 ⁇ l of 1 ,4-dioxane, 3-pentanone or diisopropyl ether. The suspension or solution is agitated using High-speed vortexer at about 45-55°C for about 2 hrs.
  • the solution is then allowed to evaporate at 45°C to 55°C under a stream of nitrogen.
  • the crystals obtained from the mixture consisting of benzyl alcohol/diisopropyl ether.
  • a DSC curve (recorded using a Perkin Elmer DSC-7 instrument with a heating rate of 10K/min and a sample mass of about 0.7mg) shows a melting event at 95°C followed by an exothermic recrystallization and a second melting at about 223°C.
  • Example 4 Preparation of crystalline form F of lmatinib Mesylate using a mixture of Benzyl Alcohol and Acetonitrile or Dimethyl Formamide
  • lmatinib mesylate is first dissolved in about 100ml of water. About 50 ⁇ l of the stock solution is dispensed manually into a CRISSY 96-well block, to have a total amount of drug substance of 5mg per well. The solution is flushed with nitrogen at room temperature to dry the solution. The dry precipitate is resuspended with a mixture of 200 ⁇ l of benzyl alcohol and 50 ⁇ l of acetonitrile or dimethyl formamide. The suspension or solution is agitated using High-speed vortexer at about 45-55°C for about 2 hrs. The solution is then allowed to evaporate at 45°C to 55 C C under a stream of nitrogen.
  • Example 5 Tablets with lmatinib mesylate, F-crystal form
  • Tablets containing 100 mg of the active substance named in the title are usually prepared in the following composition:
  • the active substance is mixed with carrier materials and compressed on a tableting machine (Korsch EKO, punch diameter 10 mm).
  • Avicel is microcrystalline cellulose (FMC, Philadelphia, USA).
  • PVPPXL is polyvinylpolypyrrolidone, cross-linked (BASF, Germany). Aerosil is silicon dioxide (Degussa, Germany).
  • Example 6 Capsules with lmatinib mesylate, F-crvstal form
  • Capsules containing 100 mg of the compound named in the title as active substance are usually prepared in the following composition:
  • the capsules are prepared by mixing the components and filling the mixture into hard gelatin capsules, size 1.
  • Example 7 Preparation of crystalline form G of lmatinib Mesylate using a mixture of 3- pentanone and cvclohexane
  • lmatinib mesylate is first dissolved in about 100ml of water. About 50 ⁇ l of the stock solution is dispensed manually into a CRISSY 96-well block, to have a total amount of drug substance of 5mg per well. The solution is flushed with nitrogen at room temperature to dry the solution. The dry precipitate is resuspended with a mixture of 125 ⁇ l of 3- pentanone and 125 ⁇ l of cyclohexane. The suspension or solution is agitated using Highspeed vortexer at about 45-55°C for about 2 hrs. The solution is then allowed to evaporate at 45°C to 55°C under a stream of nitrogen.
  • Example 8 Tablets with lmatinib mesylate. G-crystal form
  • Tablets containing 100 mg of the active substance named in the title are usually prepared in the following composition:
  • the active substance is mixed with carrier materials and compressed on a tableting machine (Korsch EKO, punch diameter 10 mm).
  • Avicel is microcrystalline cellulose (FMC, Philadelphia, USA).
  • PVPPXL is polyvinylpyrrolidone, cross-linked (BASF, Germany). Aerosil is silicon dioxide (Degussa, Germany).
  • Example 9 Capsules with lmatinib mesylate, G-crvstal form
  • Capsules containing 100 mg of the compound named in the title as active substance are usually prepared in the following composition:
  • the capsules are prepared by mixing the components and filling the mixture into hard gelatin capsules, size 1.
  • Example 10 Preparation of crystalline form H of lmatinib Mesylate using a mixture of 3- Pentanone and N.N-Dimethylformamide
  • lmatinib mesylate is first dissolved in about 100ml of water. About 50 ⁇ l of the stock solution is dispensed manually into a CRISSY 96-well block, to have a total amount of drug substance of 5mg per well. The solution is flushed with nitrogen at room temperature to dry the solution. The dry precipitate is resuspended with a mixture of 125 ⁇ l of 3- pentanone and 125 ⁇ l of N,N-dimethylformamide. The suspension or solution is agitated using High-speed vortexer at about 45-55X for about 2 hrs. The solution is then allowed to evaporate at 45°C to 55°C under a stream of nitrogen.
  • Example 11 Tablets with lmatinib mesylate, H-crvstal form
  • Tablets containing 100 mg of the active substance named in the title are usually prepared in the following composition:
  • the active substance is mixed with carrier materials and compressed on a tableting machine (Korsch EKO, punch diameter 10 mm).
  • Avicel is microcrystalline cellulose (FMC, Philadelphia, USA).
  • PVPPXL is polyvinylpolypyrrolidone, cross-linked (BASF, Germany). Aerosil is silicon dioxide (Degussa, Germany).
  • Example 12 Capsules with lmatinib mesylate, H-crystal form
  • Capsules containing 100 mg of the compound named in the title as active substance are usually prepared in the following composition:
  • the capsules are prepared by mixing the components and filling the mixture into hard gelatin capsules, size 1.
  • Example 13 Preparation of crystalline form I of lmatinib Mesylate using a mixture of Ethyl Acetate and Diethyl Ether
  • lmatinib mesylate is first dissolved in about 100ml of water. About 50 ⁇ l of the stock solution is dispensed manually into a CRISSY 96-well block, to have a total amount of drug substance of 5mg per well. The solution is flushed with nitrogen at room temperature to dry the solution. The dry precipitate is resuspended with a mixture of 125 ⁇ l of ethyl acetate and 125 ⁇ l of diethyl ether. The suspension or solution is agitated using High-speed vortexer at about 45-55°C for about 2 hrs. The solution is then allowed to evaporate at 45°C to 55°C under a stream of nitrogen.
  • Example 14 Tablets with lmatinib mesylate, l-crystal form
  • Tablets containing 100 mg of the active substance named in the title are usually prepared in the following composition: Composition
  • the active substance is mixed with carrier materials and compressed on a tableting machine (Korsch EKO, punch diameter 10 mm).
  • Avicel is microcrystalline cellulose (FMC, Philadelphia, USA).
  • PVPPXL is polyvinylpyrrolidone, cross-linked (BASF, Germany). Aerosil is silicon dioxide (Degussa, Germany).
  • Example 15 Capsules with lmatinib mesylate, l-crvstal form
  • Capsules containing 100 mg of the compound named in the title as active substance are usually prepared in the following composition:
  • the capsules are prepared by mixing the components and filling the mixture into hard gelatin capsules, size 1.
  • Example 16 Preparation of crystalline form K of lmatinib Mesylate using a mixture of Ethyl Acetate and N,N-Dimethylformamide
  • lmatinib mesylate is first dissolved in about 100ml of water. About 50 ⁇ l of the stock solution is dispensed manually into a CRISSY 96-well block, to have a total amount of drug substance of 5mg per well. The solution is flushed with nitrogen at room temperature to dry the solution. The dry precipitate is resuspended with a mixture of 125 ⁇ l of 3- ethyl acetate and 125 ⁇ l of N,N-dimethylformamide. The suspension or solution is agitated using High-speed vortexer at about 45-55°C for about 2 hrs. The solution is then allowed to evaporate at 45°C to 55°C under a stream of nitrogen.
  • Example 17 Tablets with lmatinib mesylate. K-crvstal form
  • Tablets containing 100 mg of the active substance named in the title are usually prepared in the following composition:
  • the active substance is mixed with carrier materials and compressed on a tableting machine (Korsch EKO, punch diameter 10 mm).
  • Avicel is microcrystalline cellulose (FMC, Philadelphia, USA).
  • PVPPXL is polyvinylpolypyrrolidone, cross-linked (BASF, Germany). Aerosil is silicon dioxide (Degussa, Germany).
  • Example 18 Caosules with lmatinib mesylate, K-crvstal form Capsules containing 100 mg of the compound named in the title as active substance are usually prepared in the following composition:
  • the capsules are prepared by mixing the components and filling the mixture into hard gelatin capsules, size 1.

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Abstract

La présente invention concerne la forme cristalline F, la forme cristalline G, la forme cristalline H, la forme cristalline I et la forme cristalline K du sel d'addition d'acide méthanesulfonique du 4-(4-méthylpipérazin-1-ylméthyl)- N-[4-méthyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phényl]-benzamide, certains procédés de synthèses desdites formes, des préparations pharmaceutiques contenant ces formes cristallines, leur utilisation dans des méthodes diagnostiques ou pour le traitement thérapeutique d'animaux à sang chaud, et leur utilisation en tant qu'intermédiaires ou pour l'élaboration de préparations pharmaceutiques pouvant être employées dans des méthodes diagnostiques ou pour le traitement thérapeutique d'animaux à sang chaud, en particulier des humains.
PCT/EP2006/011240 2005-11-25 2006-11-23 Formes cristallines f, g, h, i et k du mésylate d’imatinib WO2007059963A1 (fr)

Priority Applications (17)

Application Number Priority Date Filing Date Title
US12/094,629 US7893076B2 (en) 2005-11-25 2006-11-23 Crystalline form F of Imatinib mesylate
KR1020137031543A KR20130141712A (ko) 2005-11-25 2006-11-23 이마티니브 메실레이트의 ｆ, ｇ, ｈ, ｉ 및 ｋ 결정형
KR1020137031544A KR20130140909A (ko) 2005-11-25 2006-11-23 이마티니브 메실레이트의 ｆ, ｇ, ｈ, ｉ 및 ｋ 결정형
BRPI0618993-8A BRPI0618993A2 (pt) 2005-11-25 2006-11-23 formas de cristais f, g, h, i e k de mesilato de imatinib
JP2008541641A JP5844508B2 (ja) 2005-11-25 2006-11-23 メシル酸イマチニブのｆ結晶形
CN2006800440077A CN101312960B (zh) 2005-11-25 2006-11-23 甲磺酸伊马替尼的f、g、h、i和k晶形
CA2628330A CA2628330C (fr) 2005-11-25 2006-11-23 Formes cristallines f, g, h, i et k du mesylate d'imatinib
EP06818763A EP1960380A1 (fr) 2005-11-25 2006-11-23 Formes cristallines f, g, h, i et k du mésylate d imatinib
AU2006316823A AU2006316823A1 (en) 2005-11-25 2006-11-23 F,G,H,I and K crystal forms of imatinib mesylate
KR1020137031545A KR20130137721A (ko) 2005-11-25 2006-11-23 이마티니브 메실레이트의 ｆ, ｇ, ｈ, ｉ 및 ｋ 결정형
NO20082684A NO20082684L (no) 2005-11-25 2008-06-16 F-, G-, H-, I- og K-krystallformer av imatinibmesylat
US13/006,505 US8198289B2 (en) 2005-11-25 2011-01-14 Crystal form H imatinib mesylate for pharmaceutical use
AU2011201286A AU2011201286A1 (en) 2005-11-25 2011-03-22 F,G,H,I and K crystal forms of imatinib mesylate
US13/183,557 US8507515B2 (en) 2005-11-25 2011-07-15 Crystalline form G of imatinib mesylate
US13/183,572 US8592440B2 (en) 2005-11-25 2011-07-15 Crystalline form I of imatinib mesylate
US13/183,600 US8846706B2 (en) 2005-11-25 2011-07-15 Crystalline form K of imatinib mesylate
US13/472,000 US8633213B2 (en) 2005-11-25 2012-05-15 Crystalline form F of imatinib mesylate

Applications Claiming Priority (10)

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GB0524062A GB0524062D0 (en) 2005-11-25 2005-11-25 Organic compounds
GB0524062.7 2005-11-25
GB0524061A GB0524061D0 (en) 2005-11-25 2005-11-25 Organic compounds
GB0524061.9 2005-11-25
US74001705P 2005-11-28 2005-11-28
US74001605P 2005-11-28 2005-11-28
US74001805P 2005-11-28 2005-11-28
US60/740,016 2005-11-28
US60/740,017 2005-11-28
US60/740,018 2005-11-28

Related Child Applications (2)

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US12/094,629 A-371-Of-International US7893076B2 (en) 2005-11-25 2006-11-23 Crystalline form F of Imatinib mesylate
US13/006,505 Division US8198289B2 (en) 2005-11-25 2011-01-14 Crystal form H imatinib mesylate for pharmaceutical use

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US (6) US7893076B2 (fr)
EP (3) EP1960380A1 (fr)
JP (2) JP5844508B2 (fr)
KR (4) KR20130137721A (fr)
CN (1) CN102351842B (fr)
AU (2) AU2006316823A1 (fr)
BR (1) BRPI0618993A2 (fr)
CA (3) CA2824307C (fr)
EC (1) ECSP088473A (fr)
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NO (1) NO20082684L (fr)
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JP2010540465A (ja) * 2007-09-25 2010-12-24 テバ ファーマシューティカル インダストリーズ リミティド 安定なイマチニブ組成物
WO2011023146A1 (fr) 2009-08-26 2011-03-03 Zentiva, K.S. Polymorphes de mésylate d'imatinib générés par cristallisation dans des solutions salines inorganiques aqueuses
WO2011049474A1 (fr) 2009-10-22 2011-04-28 Tomasz Kozluk Sels d'imatinib avec des acides tartriques
WO2011099039A1 (fr) 2010-02-15 2011-08-18 Reliance Life Sciences Pvt. Ltd. Procédé pour la préparation d'une forme alpha de mésylate d'imatinib
WO2011108953A1 (fr) 2010-03-04 2011-09-09 Tomasz Kozluk Procédé pour la préparation de forme polymorphe α et nouvelle forme polymorphe d'imatinib mésylate isolée dans ce procédé
WO2012090221A1 (fr) 2010-12-29 2012-07-05 Cadila Healthcare Limited Nouveaux sels d'imatinib
EP2604596A1 (fr) * 2011-12-16 2013-06-19 Deva Holding Anonim Sirketi Polymorphes d'imatinib
WO2013189910A1 (fr) 2012-06-22 2013-12-27 Basf Se Cristaux multicomposants comprenant du mésilate d'imatinib et des agents de co-cristallisation choisis
EP2803352A1 (fr) 2013-05-14 2014-11-19 Hetero Research Foundation Compositions d'imatinib

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CN102351842B (zh) * 2005-11-25 2014-07-23 诺华股份有限公司 甲磺酸伊马替尼的f、g、h、i 和k晶形
KR101242955B1 (ko) * 2012-06-25 2013-03-12 제일약품주식회사 이마티닙 메실레이트 결정형 α의 제조 방법
WO2015081175A1 (fr) * 2013-11-26 2015-06-04 Children's Medical Center Corporation Valve d'endoprothèse extensible
PL3539138T3 (pl) 2016-11-11 2021-12-13 Curium Us Llc Sposoby generowania germanu-68 ze zmniejszoną ilością części lotnych
JP7263784B2 (ja) 2019-01-11 2023-04-25 日本精工株式会社 自在継手用ヨーク

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JP2010540465A (ja) * 2007-09-25 2010-12-24 テバ ファーマシューティカル インダストリーズ リミティド 安定なイマチニブ組成物
KR101041203B1 (ko) * 2007-09-25 2011-06-13 테바 파마슈티컬 인더스트리즈 리미티드 안정한 이매티닙 조성물
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WO2011023146A1 (fr) 2009-08-26 2011-03-03 Zentiva, K.S. Polymorphes de mésylate d'imatinib générés par cristallisation dans des solutions salines inorganiques aqueuses
WO2011049474A1 (fr) 2009-10-22 2011-04-28 Tomasz Kozluk Sels d'imatinib avec des acides tartriques
WO2011099039A1 (fr) 2010-02-15 2011-08-18 Reliance Life Sciences Pvt. Ltd. Procédé pour la préparation d'une forme alpha de mésylate d'imatinib
WO2011108953A1 (fr) 2010-03-04 2011-09-09 Tomasz Kozluk Procédé pour la préparation de forme polymorphe α et nouvelle forme polymorphe d'imatinib mésylate isolée dans ce procédé
WO2012090221A1 (fr) 2010-12-29 2012-07-05 Cadila Healthcare Limited Nouveaux sels d'imatinib
EP2604596A1 (fr) * 2011-12-16 2013-06-19 Deva Holding Anonim Sirketi Polymorphes d'imatinib
WO2013189910A1 (fr) 2012-06-22 2013-12-27 Basf Se Cristaux multicomposants comprenant du mésilate d'imatinib et des agents de co-cristallisation choisis
US9221789B2 (en) 2012-06-22 2015-12-29 Basf Se Multicomponent crystals comprising imatinib mesilate and selected co-crystal formers
EP2803352A1 (fr) 2013-05-14 2014-11-19 Hetero Research Foundation Compositions d'imatinib

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CA2824301A1 (fr) 2007-05-31
AU2006316823A1 (en) 2007-05-31
JP2009517353A (ja) 2009-04-30
CA2628330A1 (fr) 2007-05-31
CA2824307C (fr) 2016-03-29
ECSP088473A (es) 2008-06-30
AU2011201286A1 (en) 2011-04-07
KR20080078804A (ko) 2008-08-28
MY146403A (en) 2012-08-15
US20120226038A1 (en) 2012-09-06
KR20130141712A (ko) 2013-12-26
US20120015955A1 (en) 2012-01-19
UY29964A1 (es) 2007-06-29
BRPI0618993A2 (pt) 2011-09-20
US8846706B2 (en) 2014-09-30
EP1960380A1 (fr) 2008-08-27
CA2628330C (fr) 2015-06-16
US20120015027A1 (en) 2012-01-19
US8507515B2 (en) 2013-08-13
EP2546248A1 (fr) 2013-01-16
US7893076B2 (en) 2011-02-22
US8633213B2 (en) 2014-01-21
US20110171301A1 (en) 2011-07-14
NO20082684L (no) 2008-08-15
EP2578580A1 (fr) 2013-04-10
US20080268040A1 (en) 2008-10-30
CA2824307A1 (fr) 2007-05-31
KR20130137721A (ko) 2013-12-17
CN102351842A (zh) 2012-02-15
CN102351842B (zh) 2014-07-23
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US20130224288A1 (en) 2013-08-29

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